The World Health Organization Fact Sheet (No. 194, revised January 2002) notes that the bacterial infections which contribute most to human diseases are also those in which emerging microbial resistance is most evident: diarrhoeal diseases, respiratory tract infections, meningitis, sexually transmitted infections, and hospital-acquired infections. Some important examples of bacteria resistant to typical antibacterial agents include: penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, and methicillin-resistant Staphylococcus aureus. However β-lactam, fluoroquinolones and aminoglycoside resistance in Gram negatives is currently posing the greatest challenge to clinicians. β-lactam antibiotics have conventionally remained the mainstay of therapy for the management of wide range of Gram-negative infections, including those caused by Klebsiella, Escherichia coli, Enterobacter, Serratia, P. aeruginosa etc.
The problem of emerging drug-resistance in bacteria is often tackled by switching to next-line of antibacterial agents, which can be more expensive and sometimes more toxic. However, even this may not be a permanent solution and the bacteria often develop resistance to the newer antibacterial agents in due course. Bacteria are particularly efficient in developing resistance, because of their ability to multiply very rapidly and pass on the resistance genes as they replicate.
Several antibacterial combinations have been studied in the prior art including those by Mayer et al. (Investigation of the aminoglycosides, fluoroquinolones and third-generation cephalosporin combinations against clinical isolates of Pseudomonas spp. J. Antimicrob. Chemother., 43, 651-657, 1999); Gradelski et al. (Synergistic activities of gatifloxacin in combination with other antibacterial agents against clinical isolates of Pseudomonas aeruginosa and related species. Antimicrob. Agents Chemother., 45, 3220-3222, 2001); Fish et al. (Synergistic activity of cephalosporins plus fluoroquinolones against Pseudomonas aeruginosa with resistance to one or both drugs. J. Antimicrob. Chemother., 50, 1045-1049, 2002) and Davis et al. (In vitro activity of gatifloxacin alone and in combination with cefepime, meropenem, piperacillin and gentamicin against multidrug-resistant organisms, J. Antimicrob. Chemother., 51, 1203-1211, 2003). Fish et al. found combination of cefepime or ceftazidime with ciprofloxacin, levofloxacin, gatifloxacin or moxifloxacin synergistic against 10 clinical Pseudomonas aeruginosa strains including those resistant to both cephalosporins and fluoroquinolones. In another study, N. Sivagurunathan et al. (Synergy of gatifloxacin with cefoperazone and cefoperazone-sulbactam against resistant strains of Pseudomonas aeruginosa. J. Medical Microb., 57, 1514-1517, 2008) obtained in vitro synergy with gatifloxacin and cefoperazone and gatifloxacin-cefoperazone-sulbactam combination against resistant strains of Pseudomonas aeruginosa. In few cases, these antibiotic combinations have also been successfully employed as an effective treatment for Pseudomonas aeruginosa nosocomial infections (Al-Hasan et. al, β-Lactam and Fluoroquinolone combination antibiotic therapy for bateremia caused by Gram-negative bacilli. Antimicrob. Agents Chemother., 53(4), 1386-1394, 2009).
Bacteria use several mechanisms to acquire resistance to antibacterial agents including, such as for example, drug inactivation or modification (e.g. enzymatic deactivation of Penicillin G in some penicillin-resistant bacteria through the production of β-lactamases), alteration of target site (e.g. alteration of PBP, the binding target site of penicillins in MRSA and other penicillin-resistant bacteria), alteration of metabolic pathway (e.g. some sulfonamide-resistant bacteria do not require para-aminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides) or reduced accumulation of antibacterial agents through efflux pumps (e.g. by decreasing permeability and/or increasing active efflux of the antibacterial agents across the cell surface).
There are four primary mechanisms by which bacteria can overcome β-lactam antibiotics: (i) production of β-lactamases; (ii) mutations in the target PBPs; (iii) decreased expression of outer membrane proteins/porins; and (iv) efflux pumps. Production of β-lactamases is the main mechanism of resistance to this class of antibiotic. Introduction of extended spectrum ⊖-lactams during 1980s were responded by Gram-negative organisms with the production of extended spectrum β-lactamases (ESBLs). ESBLs are plasmid mediated β-lactamases, known as extended spectrum, because they are able to hydrolyze a broader spectrum of β-lactam antibiotics including third and fourth generation cephalosporins.
Resistance to β-lactams, β-lactams-β-lactamsase-inhibitors, cephalosporins and monobactam is wide spread. Such resistance challenges the ability to treat serious urinary tract infection, respiratory tract infections and blood stream infections. Internationally, the prevalence of ESBL in Klebsiella and E. coli is in the range of 30-50% depending upon the geographical location. For ESBLs, carbapenem therapy is most widely used in the clinical settings today. Presently, all strains identified as inhibitor resistant ESBLs are treated only by carbapenems. This extensive and widespread use of carbapenems has triggered the selection of carbapenem resistant strains.
Therefore, there is a need for development of compositions capable of acting against ESBLs, which are currently resistant to available β-lactam-β-lactamase inhibitor (and can only be treated by carbapenems). Surprisingly, it has been found that a pharmaceutical composition comprising effective amount of an antibacterial agent and tazobactam or a pharmaceutically acceptable salt thereof, in a specific ratio of tazobactam to the antibacterial agent in the composition, exhibits unexpectedly improved antibacterial efficacy, even against highly resistant ESBL producing gram negative pathogens.